Parkinson's disease is the most common neurodegenerative movement disorder and is characterized pathologically by the intraneuronal deposition of abnormally phosphorylated and aggregated ?-synuclein protein. Abnormal deposition of ?-synuclein into neuronal and glial aggregates is also the primary pathologic feature of a group of collectively even more common disorders, termed the ?-synucleinopathies. To define the molecular mechanisms controlling ?-synuclein induced neurodegeneration we and others have modeled ?-synucleinopathies in the simple and powerful genetic model organism Drosophila. Genetic, biochemical and cell biological experiments in Drosophila have provided important clues regarding the pathogenesis of ?-synucleinopathies. However, the unbiased forward genetic screens providing the bases for these studies, while valuable, have to date remained incomplete. Here we propose to use a newly created and powerful Drosophila model of ?-synucleinopathies to perform a comprehensive genetic analysis of ?-synuclein neurotoxicity in vivo. These studies will for the first time provide a broad analysis of mechanisms controlling ?-synuclein toxicity to postmitotic neurons and should identify many new high-value therapeutic targets. Our studies will be particularly important as more and more data emerges from genome wide associated studies showing genetic influences on Parkinson's disease and related ?-synucleinopathies, but with little clear evidence as to the mechanism of action of these newly identified gene products in neurodegenerative disease pathogenesis.